Carbovir (EP 00,434,450 and EP 00,349,242) along with abacavir are well known anti-HIV carbocyclic nucleosides. Abacavir is the most potent nucleoside reverse transcriptase inhibitor (NRTI) developed to date. An average reduction in viral load of more than 1.4 log 10 RNA copies/ml is observed after a short course of abacavir monotherapy.

Dideoxynucleotide use such as dideoxycytidine (ddC) and of didehydrodideoxythymidine (d4T) is limited by associated painful sensory-motor peripheral neuropathy. Dideoxyinosine also shares this complication as well as causing acute pancreatitis, and hepatotoxicity in some cases (Maag, H. et al., J. Med. Chem., 1992, 35, 1440). Yet another concern about this class of compounds has been the emergence of resistant HIV strains in patients undergoing treatment with nucleosides. For instance the ddI-resistant strains were also shown to be resistant to ddC. In another study, clinical HIV isolates resistant to AZT displayed marked resistance to d4T. It appears, then, that some cross resistance is inevitable among this class of similar nucleoside structures. Therefore, an important criterion for the design of any new nucleoside drug would be a distinct dissimilarity of structure to the current family of dideoxynucleosides.
Substitution at the 4′ position of nucleosides has been reported to exert potent antiviral activity against HIV-1 as demonstrated by 4′-azido-2′-deoxythymidine (4′-AZT) (Maag, H. et al., J. Med. Chem., 1992, 35, 1440). In addition, 4′-ethynyl nucleoside analogs have been shown to be active against a wide spectrum of HIV viruses, specifically against HIV-1 M184V and HIV-1 M184I (Kodama, E. I. et al., Antimicrob. Agents Chemother., 2001, 1539). Recently, Haraguchi et al. reported the preparation of 4′-substituted d4T analogs. They demonstrated that contrary to the previous reports, the 3′-hydroxy group is not necessary for the 4′-substituted nucleosides to be active against HIV (Haraguchi, K. et al., Bioorg. Med. Chem. Lett., 2003, 13, 3775).
There is currently a need for therapeutic antiviral agents having unique structural characteristics. Additionally, there is a need for antiviral agents with improved pharmacological properties, e.g., drugs having improved antiviral activity and pharmacokinetic properties, including improved oral bioavailability, greater potency and extended effective half-life in vivo.